The threat of exposure to ionizing radiation from a nuclear reactor accident, nuclear attack, or deliberate terrorist actions including the detonation of dirty bombs is a significant public healh concern. The lung is particularly susceptible to ionizing radiation injury from external sources or inhalation of radioactive particles from radioactive fall-out. Radiation pneumonopathy can manifest with an acute radiation pneumonitis and/or delayed effects of acute radiation exposure (DEARE) leading to progressive, often fatal pulmonary fibrosis. Medical countermeasures (MCMs) to mitigate radiation-pneumonopathy are needed; the ideal treatment is one that can be given in a mass-casualty situation many hours post-exposure, as prior warning is unlikely. Discovery Laboratories, Inc., a biotechnology company (small business concern) is evaluating its proprietary peptide-based synthetic KL4 surfactant (lucinactant) as a broad-spectrum, multi-use MCM against chemical, biological, radiological and nuclear threat agents targeting the lung. Given KL4 surfactant's lung-protective and immune-modulatory properties, ability to be delivered as an aerosol to spontaneously breathing subjects, and its robustness (resistance to inactivation by plasma proteins and oxidants present in the inflamed lung), the drug is an ideal MCM test candidate to treat radiation pneumonopathy. Moreover, the extensive preclinical and clinical safety/efficacy experience with KL4 surfactant (>1000 treated patients), and its potential FDA approval in early 2012 for prevention of neonatal RDS should facilitate the regulatory approval of the drug as a MCM. Exogenous surfactants have not been evaluated for treating radiation pneumonopathy. Our objectives are to evaluate KL4 surfactant as a novel approach to mitigate radiation pneumonopathy in the well characterized C57BL/6 mouse model. Discovery Labs will be collaborating with Dr. Christofidou-Solomidou at Univ. of Pennsylvania, who is well published in the area, and who has collaborated and previously published with Dr. Segal (PI) on KL4 surfactant to mitigating acute lung injury in C57BL/6 mouse models. We hypothesize that KL4 surfactant, when delivered to the lung 24 hours post high-dose radiation, will mitigate radiation pneumonopathy. The Specific Aims are test in the C57BL/6 thoracic-radiation mouse model whether KL4 surfactant delivered for 2 weeks beginning 24 hours post irradiation can reduce: 1) acute radiation pneumonitis (protein leak, neutrophil/macrophage migration, cytokine production) observed at day 21 post exposure; 2) the delayed subacute inflammatory response and altered lung architecture/fibrosis (including histopathology, hydroxyproline content, and indicators of oxidative stress), observed at week 18 post exposure. These proof- of-concept experiments should determine whether KL4 surfactant should be further evaluated (alone or with other mitigating agents), which could be supported by a SBIR Phase II funding mechanism. The long-term objective is to obtain FDA approval of KL4 surfactant as a MCM for radiation pneumonopathy, and its inclusion in the Strategic National Stockpile for treating radiation exposure, an important goal of Project Bioshield.